Psoriatic arthritis (PsA), is an inflammatory musculoskeletal disease than can lead to joint damage and disability and up to 45% of patients don't respond to biologic therapies. Major hurdles are a limited understanding of mechanisms causing inflammation and bone damage and the absence of markers that predict treatment response. Circulating osteoclast (OC) precursors (OCP), progenitors of bone resorbing OC, are increased in PsA blood and joints and these cells express membrane DC-STAMP, a molecule required for OCgenesis. DC-STAMP has an inhibitory motif (ITIM) in the cytoplasmic tail that regulates signaling. Our overarching hypothesis is that DC-STAMP regulates multiple steps during OCgenesis, has strong potential as a therapeutic target and may serve as an early response marker in inflammatory arthritis. To address these hypothesis, we plan 3 Specific Aims: Aim1: Regulation of cell-fusion and signaling by DC-STAMP during OCgenesis. Hypothesis: DC-STAMP is essential for early cell fusion, but negatively regulates late-stage osteoclastogenesis via ITIM inhibition of Ca+2 signaling and NFATc1 activation. To test this hypothesis, we will light activate chimeric rhodopsin-DC- STAMP chimeras with and without the ITIM, transfected into DC-STAMP-/-murine macrophages and analyze the ITIM effect on cell fusion and downstream signaling at different time points during OCgenesis. Aim2:Functional characterization of DC-STAMP+ monocytes in murine arthritis . Hypothesis: DC-STAMP+ monocytes promote synovial inflammation and bone destruction in the TNF-Tg mouse model of inflammatory-erosive arthritis. To test this hypothesis, bone marrow cells from WT or DC- STAMP-/- mice linked to GFP will be transferred into lethally-irradiated TNF-Tg mice and TNF-Tg bone marrow into irradiated DC-STAMP-/- mice. Joint inflammation and damage will be evaluated by clinical evaluation, Doppler Power ultrasound (PDUS)/micro-CT, and histologic analysis at different time points. The ability of the DC-STAMP 1A2 Ab to ameliorate or prevent arthritis onset will also be analyzed in these mice. Aim3: Assessment of DC-STAMP as an early treatment response marker in PsA. Hypothesis: Change in monocyte DC-STAMP expression at 2 weeks will predict long-term response to TNFi. To test this hypotheses, DC-STAMP monocyte expression in PsA and PDUS of inflamed joints will be assessed at baseline, 2 and 16 weeks after starting a TNFi or MTX. The primary outcome measure will be the change in the Disease Activity in PsA (DAPSA) at 16 weeks. The change in DC-STAMP at 2 weeks will be correlated with change in DAPSA and PDUS scores at 16 weeks. These studies will provide insights into key mechanisms that underlie PsA and catalyze biomarker discovery. Our results will also lead to therapies that target the DC-STAMP signaling pathway with potential to impede pathologic bone degradation in PsA, osteoporosis and other inflammatory bone and joint disorders.